Current therapies for CMV retinitis (CMV-R) are far from optimal. Although the incidence of CMV-R has declined since the advent of HAART, many AIDS experts believe that it will become more frequent in the future. This is because of the increased prevalence of persons living with HIV infection (nearly 1 million Americans), the 5 percent to 10 percent estimated annual rate of development of resistance to HAART, as well as the fact that substantial percentages of unselected patients fail to respond to HAART. Thus, it would be prudent to develop better methods for treating CMV-R. The overall goal of the re-revised competing renewal of EY1 1832 is to design, evaluate and optimize prodrugs with activity against CMV for an oral therapy for CMV-R. During the first 3 years, derivatives of ganciclovir (GCV) and foscarnet (PFA) were found to be active for 4 weeks or longer after a single intravitreal injection. An oral prodrug of GCV was discovered which is active against murine CMV, acute HSV-1 infection in mice, and in SCID-hu mice with HCMV-infected human retinal implants. Recently 1 -O-hexadecylpropanediol-3-cCDV, a highly active analog of cyclic Cidofovir (cCDV) has been synthesized and found to have a subnanomolar IC50 against HCMV and a selectivity index of >50,000. The compound is similar in design to orally bioavailable prodrugs of GCV. Generally stated, the specific aims of the re-revised proposal are to carry out structure-activity assessments of the in vitro activity and selectivity of lipid prodrugs of GCV and CDV designed and optimized for oral therapy of HCMV infection and to evaluate the safety parameters in vitro and in vivo and efficacy in HCMV retinitis in SCID-mice in vivo. Oral pharmacokinetics and toxicology of selected GCV and CDV prodrugs will be assessed in rodents, followed by testing for oral efficacy in SCID-hu mice with human HCMV-infected retinal implants or in murine CMV infection in mice. Since many AIDS experts believe that CMV-retinitis has reached a temporary nadir and will increase in the future, this research has direct health-related significance both to those Americans living with HIV infection and to organ transplant patients at risk for CMV disease because of their need for immunosuppresive drugs to prevent organ rejection.